OBJECTIVE To test the hypothesis that since only a proportion of heavy drinkers develop significant alcoholic liver disease (ALD), an autoimmune pathogenesis is likely. METHODS Autoimmune markers were measured in 47 patients with biopsy-proven ALD and compared to measurements in 20 alcoholics without clinical and hematologic evidence of ALD and 28 patients with autoimmune chronic active hepatitis (CAH). RESULTS Twenty-two percent of patients with ALD were antinuclear antibody-positive, compared to 71% of patients with CAH. Approximately 60% of patients with ALD had either anti-single-stranded or anti-double-stranded DNA antibodies, slightly more than the patients with CAH. Another marker of autoimmunity, as in systemic lupus erythematosus, is the presence of IgM antibodies to autologous and heterologous lymphocytes, which are cytotoxic at 4 degrees C. Seventy-two percent of patients with CAH had positive antilymphocyte antibodies, compared to 59.6% of patients with ALD. Furthermore, more than 90% of the sera from ALD and CAH patients displayed lymphocytotoxicity. Thirty-two percent and 25.5% of CAH and ALD patients, respectively, had all three autoantibodies present. CONCLUSIONS These results suggest that autoimmune mechanisms may indeed play a role in the pathogenesis of ALD in at least some patients.